1. Field of the Invention
The present invention provides novel mitomycin analogs containing a disulfide group (Class 260, Subclass 326.24) and processes for the preparation thereof. These compounds are mitomycin A analogs in which the 7-alkoxy group bears an organic substituent incorporating a disulfide group. The present invention also provides a method of producing mitomycin A and derivatives thereof (Class 260, Subclass 326.24). Mitomycin A is an antibiotic of established utility, and the 7-O-substituted mitosane analogs thereof have similar utility.
Nomenclature--The systematic Chemical Abstracts name for mitomycin A based on the recent revision [Shirhata et al., J. Am. Chem. Soc., 105, 7199 (1983)] is:
[1aS-(1a.beta., 8.beta., 8a.alpha., 8.beta.b.beta.)]-8-[((aminocarbonyl)oxy)methyl]-6,8a-dimethoxy-1,1a,2,8,8a ,8b-hexahydro-5-methy]-arizino[2',3',3,4,]pyrrolo[1,2-a]indole-4,7-dione according to which the azirinopyrroloindole ring system is numbered as follows: ##STR1##
A trivial system of nomenclature which has found wide use in the mitomycin literature identifies the foregoing ring system including several of the characteristic substituents of the mitomycins as mitosane. ##STR2## According to this system, mitomycin A is 7,9a-dimethoxymitosane and mitomycin C is 7-amino-9a-methoxymitosane. As to the stereochemical configuration of the products of this invention, it is intended when identifying them by the root name "mitosane" or by structural formula to identify the stereochemical configuration thereof as the same as that of mitomycin A or C. ##STR3##
2. Disclosure Statement
Mitomycin C is an antibiotic which is produced by fermentation and is presently on sale under Food and Drug Administration approval in the therapy of disseminated adenocarcinoma of the stomach or pancreas in proven combinations with other approved chemotherapeutic agents and as palliative treatment when other modalities have failed (Mutamycin.RTM. Bristol Laboratories, Syracuse, New York 13221, Physicians' Desk Reference 37th Edition, 1983, pp. 747 and 748). Mitomycin C and its production by fermentation is the subject of U.S. Pat. No. 3,660,578 patented May 2, 1972 claiming priority from earlier applications including an application filed in Japan on Apr. 6, 1957.
The structures of mitomycins A, B, C, and of porfiromycin were first published by J. S. Webb et al. of Lederle Laboratories Division American Cyanamid Company, J. Am. Chem. Soc., 84, 3185-3187 (1962). One of the chemical transformations used in this structure study to relate mitomycin A and mitomycin C was the conversion of the former, 7,9a-dimethoxymitosane, by reaction with ammonia to the latter, 7-amino-9a-methoxymitosane. Displacement of the 7-methoxy group of mitomycin A has proven to be a reaction of considerable interest in the preparation of antitumor active derivatives of mitomycin C. Recently the stereochemical configurations of positions 1, 1a, 8a and 8b have been shown to be as indicated above with respect to the Chemical Abstracts nomenclature [Shirhata et al., J. Am. Chem. Soc., 105, 7199-7200 (1983)]. The earlier literature- refers to the enantiomer.
The following articles and patents deal inter alia with the conversion of mitomycin A to a 7-substituted amino mitomycin C derivative having antitumor activity. The object of this research was to prepare derivatives which were more active, and particularly which were less toxic than mitomycin C:
Matsui et al., J. Antibiotics, XII, 189-198 (1968); PA1 Konishita et al., J. Med. Chem. 15, 103-109 (1971); PA1 Iyengar al., J. Med. Chem., 24, 975-981 (1981); PA1 Cosulich et al., U.S. Pat. No. 3,332,944, issued July 25, 1967; PA1 Matsui et al., U.S. Pat. No. 3,420,846, issued Jan. 7, 1969; PA1 Matsui al., U.S. Pat. No. 3,450,705, issued June 17, 1969; PA1 Matsui et al., U.S. Pat. No. 3,514,452, issued May 26, 1970; PA1 Nakano al., U.S. Pat. No. 4,231,936, issued Nov. 4, 1980; PA1 Remers, U.S. Pat. No. 4,268,676, issued May 19, 1981. PA1 Kono et al., European Patent Application No. 116,208 (1984); PA1 Vyas et al., U.K. Patent Application No. 2,140,799 (1984). PA1 Alk.sub.2 is a straight or branched chain alkylene group having 2 to 6 carbon atoms optionally bearing an A substituent wherein the sulfur and oxygen atoms connected thereto and any optional A substituent connected thereto through oxygen, sulfur or nitrogen are attached to different carbon atoms of Alk.sub.2, wherein said A substituent is selected from the group consisting of one or two C.sub.1-6 alkyl, C.sub.1-6 alkanoyl, C.sub.1-6 alkoxy, halogen, C.sub.1-6 alkoxycarbonyl, cyano, C.sub.1-6 alkylamin C.sub.1-6 -dialkylamino, C.sub.1-6 alkanoylamino and C.sub.1-6 alkoxycarbonyl, PA1 Alkl.sub.1 and Alk.sub.2 may contain a double bond, PA1 R.sup.1 is hydrogen, lower alkyl, lower alkanoyl, benzoyl or substituted benzoyl wherein said substituent is lower alkyl, lower alkoxy, halogen, amino or nitro, PA1 R.sup.3 is selected from the group consisting of halogen, carboxy, alkanoyloxy having 1 to 7 carbon atoms, hydroxy wherein the oxygen atom is connected to Alkl.sub.1 having 3 to 6 carbon atoms, alkylamino or dialkylamino having 1 to 12 carbon atoms, N-alkoxy-alkylamino having 2-7 carbon atoms, alkanoylamino having 1-7 carbon atoms, benzoylamino or B-substituted benzoylamino, naphthoylamino or B-substituted naphthoylamino, phenylamino or B-substituted phenylamino, cycloalkyl or B-substituted cycloalkyl each having 3 to 8 ring members, cycloalkenyl or B-substituted cycloalkenyl each having 5 to 8 ring members, phenyl or B-substituted phenyl, naphthyl or B-substituted naphthyl, a heterocyclic group selected from the group consisting of heteroaromatic and heteroalicyclic groups having from 1 to 2 rings, from 3 to 8 ring members in each ring and from 1 to 2 heteroatoms in each ring selected from oxygen, nitrogen and sulfur, pyridylamino or thiazolylamino, alkoxy or alkylthio each having 1 to 6 carbon atoms, alkoxycarbonyl or alkylaminocarbonyl each having 2 to 7 carbon atoms, aminocarbonyl, phenoxycarbonyl or B-substituted phenoxycarbonyl, phenoxy or B-substituted phenoxy- naphthoxy or B-substituted naphthoxy, alkoxycarbonylamino having 2 to 6 carbon atoms, ureido (--NHCONH.sub.2), N-alkylureylene (--NHCONHalkyl) having 2 to 7 carbon atoms, N.sup.3 -haloalkylureylene having 3 to 7 carbon atoms, N.sup.3 -haloalkyl-N.sup.3 -nitrosoureylene having 3 to 7 carbon atoms, dialkylaminocarbonyl having 3 to 13 carbon atoms, dialkylaminoalkoxy having 4 to 13 carbon atoms, alkanoylaminoalkoxy having 3 to 7 carbon atoms and hydroxyalkylamino or N,N-dihydroxyalkyl amino each having 2 to 8 carbon atoms, wherein said B substituent is selected from the group consisting of one or two lower alkyl, lower alkanoyl, lower alkoxy, halogen, amino, carboxy, hydroxy and nitro groups, and PA1 R.sup.4 is selected from the group consisting of alkyl having 1 to 12 carbon atoms, alkenyl or alkynyl each having 3 to 12 carbon atoms, cycloalkyl or B-substituted cycloalkyl having 3 to 8 ring members, cycloalkenyl or B-substituted cycloalkenyl each having 5 to 8 ring members, phenyl or B-substituted phenyl, naphthyl or B-substituted naphthyl, a heterocyclic group selected from the group consisting of heteroaromatic and heteroalicyclic groups having from 1 to 2 rings, from 3 to 8 ring members in each ring, and from 1 to 2 eteroatoms in each ring selected from oxygen, nitrogen and sulfur, provided that the heterocyclic group is connected through a carbon atom which is attached to at least another carbon atom (i.e., the carbon atom attached to the --SS-- may not itself be attached to two other heteroatoms), wherein said B substituent is selected from the group consisting of one or two lower alklyl, lower alkanoyl, lower alkoxy, halogen, amino, carboxyl, hydroxy or nitro groups, and R.sup.4 and the adjacent sulfur atom together constitute S-cysteinyl wherein said S-cysteinyl group may be esterified, salified or joined within a non-toxic and non-allergenic peptide, or a nontoxic pharmaceutically acceptable salt thereof. PA1 R.sup.6 is C.sub.1-12 alkyl or substituted C.sub.1 alkyl, C.sub.3-12 cycloalkyl or substituted C.sub.3-12 cycloalkyl wherein the carbon atom thereof which is attached to the mitosane 7-oxygen atom bears from 1 to 2 hydrogen atoms and said substituents are selected from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, C.sub.6-14 aroyl, cyano, trihalomethyl, amino, C.sub.1-6 monoalkylamino, C.sub.2-12 dialkylamino, C.sub.6-12 aryl, C.sub.6-12 aryloxy, C.sub.1-6 alkanoyloxy, C.sub.7-14 aroyloxy, heterocyclo having 1 or 2 rings and from 5 to 12 ring atoms including up to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and wherein each of said alkoxy, alkanoyl, aroyl, aryl, aryloxy, alkanoyloxy, aroyloxy, and heterocyclo substituents optionally contains from 1 to 2 substituents selected from halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, cyano, trihalomethyl, amino, C.sub.1-6 alkylamino, or C.sub.2-12 dialkylamino groups.
Iyengar, Sami, Remers and Bradner, Abstracts of Papers, 183rd Annual Meeting of the American Chemical Society, Las Vegas, Nevada, March 1982, Abstract No. MEDI 72;
The following patent applications deal with the preparation of 7-substituted amino mitomycin C derivatives in which the substituent incorporates a disulfide linkage.
7-Alkoxy substituted mitosanes related structurally to mitomycin A are described as useful antibiotics having activity in experimental animal tumors in an article by Urakawa et al., J. Antibiotics, 23, 804-809 (1980).
Mitomycin C is the principal mitomycin produced by fermentation and is the commercially available form. Current technology for the conversion of mitomycin C to mitomycin A suffers from a number of deficiencies. Hydrolysis of mitomycin C to the corresponding 7-hydroxy-9a-methoxy-mitosane, and then methylation of that substance requires diazomethane, a very hazardous substance to handle on a manufacturing scale, and the 7-hydroxy intermediate is very unstable [Matsui et al., J. Antibiotics, XXI, 189-198 (1968)]. One attempt to avoid these difficulties involves the use of 7-acyloxymitosanes (Kyowa Hakko Kogyo KK Japanese Patent No. J5 6073-085, Farmdoc No. 56227 D/31). Alcoholysis of mitomycin A as described by Urakawa et al., J. Antibiotics, 23, 804-809 (1980) is limited to the production of only specific 7-alkoxy structural types by the availability and reactivity of the alcohol starting materials.